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Neurophysiology of Pruritus
Interaction of Itch and Pain
Akihiko Ikoma, MD;
Roman Rukwied, PhD;
Sonja Ständer, MD;
Martin Steinhoff, MD, PhD;
Yoshiki Miyachi, MD;
Martin Schmelz, MD, PhD
Arch Dermatol. 2003;139:1475-1478.
ABSTRACT
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The discovery of an itch-specific neuronal pathway, which is distinct from the pain-processing pathway, has clarified the neuronal basis for the itch sensation. Albeit being distinct, there are complex interactions between pain and itch. The inhibition of itch by pain is well known and can explain the antipruritic effect of scratching. However, the opposite effect also exists and has major clinical implications: inhibition of pain processing (eg, by spinal opioids) can generate itch. Conversely, blockade of spinal opioid receptors can be used as an antipruritic therapy. Moreover, the spinal processing of pain and itch can be modulated, resulting in a hypersensitivity or hyposensitivity to pain or itch: similar to chronic painful conditions, ongoing activity of pruriceptors can induce a spinal hypersensitivity for itch in patients with chronic pruritus. Therapeutic antipruritic approaches therefore should target both local inflammation and spinal sensitization of itch processing.
INTRODUCTION
A former theory of itch was based on the idea that pruritus represents a subliminal version of pain (intensity theory). According to this view, weak noxious stimuli would cause minor activation of nociceptors, which should be felt as itch, whereas stronger noxious stimuli would massively excite the nociceptors and then provoke pain.1 However, recent studies have clearly shown that there is a distinct neuronal pathway for itch, functionally separated from the pain pathway. Primary afferent nerve fibers that encode histamine-induced itch were discovered in humans,2 and more recently spinal neurons were identified that specifically respond to histamine stimuli.3 The combination of dedicated peripheral and central neurons, with a unique response pattern to pruritogenic mediators4 and anatomically distinct projections to the thalamus,3 provided the basis for a specific neuronal pathway for itch.
However, the distinction between pruritic and pain-producing (algogenic) substances does not fully match the activation in pruriceptors and nociceptors; for example, the strong algogen capsaicin also activates pruriceptors.4 Although various inflammatory mediators also activate pruriceptors, concomitant activation of nociceptors will decrease itch and increase pain (for central inhibition, see the following section). Thus, the itch sensation is apparently based on both increased activity in the itch pathway and a low level of activity in the pain pathway. The relative activation of the 2 pathways will thus finally determine the perceived modality of sensation and may explain different clinical types of pruritus and pain.
PAIN INHIBITS ITCH
This interaction is in accordance with our common experience that the itch sensation can be reduced by painful scratching. The inhibition of itch by painful stimuli has also been shown experimentally by use of noxious thermal, mechanical, and chemical stimuli. Recently, electrical stimulation via an array of pointed electrodes, a method known as cutaneous field stimulation,5 has also been successfully used to inhibit histamine-induced itch for several hours in an area of 20 cm in diameter around a stimulated site. The large area of inhibition suggests a central mode of action.5 In line with these results was the observation that itch is suppressed inside the capsaicin-induced area of mechanical hyperalgesia.6 This central effect of nociceptor excitation by capsaicin should be clearly distinguished from the local neurotoxic effect of higher concentrations of capsaicin, which destroy all C-fiber terminals, including fibers that mediate itch,7 and results in an abolished itch sensation until the nerve terminals have regenerated.
There are also divergent effects of temperature on the itch perception. Histamine-induced activation of C fibers has been shown to be temperature dependent8: warming the skin may lead to an exacerbation of itch, whereas cooling can reduce the activity of the primary afferents. Apart from these local temperature effect, cooling also exerts a certain central inhibition of itch.9-10
INHIBITION OF PAIN MAY PRODUCE ITCH
Itch can be inhibited by an enhanced input of painful stimuli. However, inhibition of pain-processing neurons may also reduce their inhibitory effect and thus enhance itch.11 Clinically, spinally administered µ-opioid receptor agonists, which are widely used in the treatment of pain, typically cause segmental pruritus.12-13 Under these conditions, itch is perceived without the activation of primary afferent neurons. The generation of pruritus can therefore be explained solely by the central inhibitory effect of opioids.14 It is important to note that the spinal neurons that signal pruritic information to the thalamus (spinothalamic projection neurons) do not have spontaneous activity,3 whereas the pain-processing spinal neurons are spontaneously active, even in the absence of inputs from the periphery. Thus, one might conclude that ongoing activity in the pain-processing system tonically suppresses activity in the spinal itch-processing neurons. In this view, the activity in the pain-processing pathway prevents us from constantly feeling itch. If the pain-processing neurons are inhibited (eg, by application of opioids), the suppression of the itch neurons might become insufficient and activation of the itch pathway would result. In other words, opioids can induce pruritus by spinal disinhibition of itch. Particularly µ-opioid agonists produce itch on spinal application. Consequently, µ-opioid antagonists have been used to combat itch. Naloxone and naltrexone were successfully used to ameliorate experimental itch15 and also reduced pruritus associated with systemic disease.16-17
In contrast,  -opioids seem to have the opposite (ie, antipruritic) effect, and a potential clinical role for -opioid receptor agonists in the treatment of pruritus has been recognized.18 In a recent meta-analysis, the -opioid agonist nalbuphine has been shown to reduce µ-opioid–induced pruritus.19 This novel therapeutic concept has already been tested successfully in patients with chronic itch.20
MODULATION OF PERIPHERAL SENSITIVITY FOR PAIN AND ITCH
Inflammatory mediators such as bradykinin, serotonin, prostanoids, interleukins, and low pH may not only be peripheral mediators of itch21 but also have been demonstrated to acutely sensitize nociceptors22 so that their responses to external stimulation are facilitated and enhanced. In addition, regulation of gene expression induced by trophic factors, such as nerve growth factor, has been shown to play a major role in persistently increased neuronal sensitivity.23 Trophic factors also initiate nerve fiber sprouting and thus change the immunocytochemical structure in skin biopsy specimens. Sprouting of epidermal nerve fibers has also been reported in combination with localized pain and hypersensitivity.24-25 Similarly, increased intradermal nerve fiber density26-27 and neurotrophin levels28-29 have been found in patients with chronic pruritus,21 which also may contribute to the sensitization of nociceptors.23, 30 Thus, the mechanisms by which peripheral nociceptors proliferate and are sensitized in patients with chronic itch and chronic pain could be similar. Unfortunately, it has not yet been possible to morphologically differentiate neurons that mediate itch from those that mediate pain. Also, there is no evidence, at present, for a specific mechanism that would only sensitize itch-mediating neurons but not affect other C fibers. Therefore, peripheral mechanisms alone might not be sufficient to explain why some inflammatory changes cause pain, whereas others are characterized by intense pruritus.
MODULATION OF CENTRAL SENSITIVITY FOR PAIN AND ITCH
There is a remarkable similarity between the phenomena associated with central sensitization for pain and itch. Activity in cutaneous chemonociceptors leads not only to acute pain but additionally can sensitize spinal neurons in the dorsal horn and increase their sensitivity (hyperalgesia). Two types of mechanical hyperalgesia can be differentiated: allodynia and punctate hyperalgesia. Normally painless touching stimuli in the uninjured surroundings of a trauma are felt as painful "touch or brush-evoked hyperalgesia" (so-called allodynia). Though this sensation is mediated by myelinated mechanoreceptive units, it apparently requires ongoing activity of primary afferent C nociceptors.31-32 The second type of mechanical hyperalgesia is characterized by an increased sensitivity to pinprick stimulation being perceived as more painful in the uninjured zone around an inflammation. This is called punctate hyperalgesia. Following a trauma, it can persist for several hours, usually much longer than touch or brush-evoked allodynia.31
In itch processing, similar phenomena have been described (ie, touch or brush-evoked pruritus around an itching site) and was termed itchy skin or allokinesis.33-35 Similar to allodynia, allokinesis requires ongoing activity in primary afferents and is elicited by low-threshold mechanoreceptors (A fibers). Also, pinprick-induced itch sensations in the surroundings of pruritic skin sites (so-called hyperkinesis) have been reported following histamine iontophoresis in healthy volunteers.11
The phenomena of allokinesis and hyperkinesis are based on central sensitization and might appear to be of theoretical interest only. However, their detailed study can dramatically modify our understanding of clinical itch. Ongoing activity in pruriceptors, which could be the basis for central sensitization, has already been verified by single-fiber recordings in a patient with chronic itch.36 Under the conditions of central sensitization leading to punctate hyperkinesis, normally painful stimuli are perceived as itching. This phenomenon has already been described in patients with atopic dermatitis, who perceive normally painful electrical stimuli as itching.37 Furthermore, intradermal injection of acetylcholine, which normally provokes pain, provokes itch in patients with atopic dermatitis,38 indicating that pain-induced inhibition of itch might be compromised in these patients. Thus, in patients with chronic itch, the central processing of pruritus can be modified such that normally painful stimuli cause itch. For example, there is a variety of algogenic mediators in inflamed skin39 that could produce itch in a sensitized patient. This has major therapeutic implications, since under this condition antipruritic therapy cannot be restricted to the inhibition of pruritogens but would also have to combat algogens. Therefore, a combination of centrally acting drugs counteracting the sensitization for itch and topically acting drugs counteracting the inflammation appear to be the most promising therapeutic approach.
COMBINATION OF PERIPHERAL AND CENTRAL SENSITIZATION
In atopic dermatitis one might therefore assume a combination of peripheral and central sensitization. In the inflamed area, increased concentrations of nerve growth factor might cause local sensitization and sprouting of nociceptors. In this inflammatory process, itch fibers may become tonically activated, which leads to sensitization of the central itch processing in the spinal cord. As the peripheral nociceptors are sensitized, they can be readily activated, even by low-intensity stimulation, and therefore will generate a massively enhanced input to the spinal neurons. Under normal conditions, such increased input should generate pain sensations, which in turn would suppress itch. However, when itch processing is centrally sensitized, as observed in patients with atopic dermatitis, they may perceive the increased peripheral input from their eczematous skin not as painful sensation but as intense itch instead. In this condition, scratching may still partly inhibit itch but simultaneously the sensation provoked by the scratching can be perceived as itch by the patient and thus exacerbate pruritus. It is obvious that the latter phenomenon may promote a vicious itch-scratch cycle as typically observed in patients with atopic dermatitis.
CONCLUSIONS
There is a complex interaction between the pain- and itch-processing pathway. Peripheral and central sensitization can contribute to chronic pruritus, and it will be of major clinical interest to further investigate their contribution in different patient groups.
AUTHOR INFORMATION
Corresponding author and reprints: Martin Schmelz, MD, PhD, Department of Anesthesiology and Intensive Care Medicine, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Theodor-Kutzer Ufer 1-3, 68135 Mannheim, Germany (e-mail: martin.schmelz{at}anaes.ma.uni-heidelberg.de).
Accepted for publication July 22, 2003.
From the Department of Dermatology, Kyoto University, Kyoto, Japan (Drs Ikoma and Miyachi); Department of Anesthesiology–Mannheim, University of Heidelberg, Mannheim, Germany (Drs Rukwied and Schmelz); and Department of Dermatology, University of Muenster, Muenster, Germany (Drs Ständer and Steinhoff). The authors have no relevant financial interest in this article.
REFERENCES
1. von Frey M. Zur Physiologie der Juckempfindung. Arch Neerland Physiol. 1922;7:142-145.
2. Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjörk HE. Specific C-receptors for itch in human skin. J Neurosci. 1997;17:8003-8008.
FREE FULL TEXT
3. Andrew D, Craig AD. Spinothalamic lamina 1 neurons selectively sensitive to histamine: a central neural pathway for itch. Nat Neurosci. 2001;4:72-77.
FULL TEXT
|
ISI
| PUBMED
4. Schmelz M, Schmidt R, Weidner C, et al. Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. J Neurophysiol. 2003;89:2441-2448.
FREE FULL TEXT
5. Nilsson HJ, Levinsson A, Schouenborg J. Cutaneous field stimulation (CFS): a new powerful method to combat itch. Pain. 1997;71:49-55.
FULL TEXT
|
ISI
| PUBMED
6. Brull SJ, Atanassoff PG, Silverman DG, Zhang J, LaMotte RH. Attenuation of experimental pruritus and mechanically evoked dysesthesiae in an area of cutaneous allodynia. Somatosens Mot Res. 1999;16:299-303.
FULL TEXT
|
ISI
| PUBMED
7. Simone DA, Nolano M, Johnson T, Wendelschafer-Crabb G, Kennedy WR. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function. J Neurosci. 1998;18:8947-8954.
FREE FULL TEXT
8. Mizumura K, Koda H. Potentiation and suppression of the histamine response by raising and lowering the temperature in canine visceral polymodal receptors in vitro. Neurosci Lett. 1999;266:9-12.
FULL TEXT
|
ISI
| PUBMED
9. Bromm B, Scharein E, Darsow U, Ring J. Effects of menthol and cold on histamine-induced itch and skin reactions in man. Neurosci Lett. 1995;187:157-160.
FULL TEXT
|
ISI
| PUBMED
10. Schmelz M. Itch—mediators and mechanisms. J Dermatol Sci. 2002;28:91-96.
FULL TEXT
|
ISI
| PUBMED
11. Atanassoff PG, Brull SJ, Zhang J, et al. Enhancement of experimental pruritus and mechanically evoked dysesthesiae with local anesthesia. Somatosens Mot Res. 1999;16:291-298.
FULL TEXT
|
ISI
| PUBMED
12. Ballantyne JC, Loach AB, Carr DB. Itching after epidural and spinal opiates. Pain. 1988;33:149-160.
FULL TEXT
|
ISI
| PUBMED
13. Scott PV, Fischer HB. Intraspinal opiates and itching: a new reflex? Br Med J (Clin Res Ed). 1982;284:1015-1016.
14. Schmelz M. A neural pathway for itch. Nat Neurosci. 2001;4:9-10.
FULL TEXT
|
ISI
| PUBMED
15. Heyer G, Dotzer M, Diepgen TL, Handwerker HO. Opiate and H1 antagonist effects on histamine induced pruritus and alloknesis. Pain. 1997;73:239-243.
FULL TEXT
|
ISI
| PUBMED
16. Peer G, Kivity S, Agami O, et al. Randomised crossover trial of naltrexone in uraemic pruritus. Lancet. 1996;348:1552-1554.
FULL TEXT
|
ISI
| PUBMED
17. Wolfhagen FH, Sternieri E, Hop WC, et al. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology. 1997;113:1264-1269.
FULL TEXT
|
ISI
| PUBMED
18. Togashi Y, Umeuchi H, Okano K, et al. Antipruritic activity of the -opioid receptor agonist, TRK-820. Eur J Pharmacol. 2002;435:259-264.
FULL TEXT
|
ISI
| PUBMED
19. Kjellberg F, Tramer MR. Pharmacological control of opioid-induced pruritus: a quantitative systematic review of randomized trials. Eur J Anaesthesiol. 2001;18:346-357.
FULL TEXT
|
ISI
| PUBMED
20. Kumagai H, Sasamura H, Hayashi M, et al. Prospects for a novel opioid -receptor agonist TRK-820 in uremic pruritus. In: Yosipovitch G, ed. International Workshop for the Study of Itch. Singapore: National Skin Center; 2001:1.
21. Ständer S, Steinhoff M, Schmelz M, et al. Neurophysiology of pruritus: cutaneous elicitation of itch. Arch Dermatol. 2003;139:1463-1470.
FREE FULL TEXT
22. Kidd BL, Urban LA. Mechanisms of inflammatory pain. Br J Anaesth. 2001;87:3-11.
FREE FULL TEXT
23. Shu X, Mendell LM. Acute sensitization by NGF of the response of small-diameter sensory neurons to capsaicin. J Neurophysiol. 2001;86:2931-2938.
FREE FULL TEXT
24. Bohm-Starke N, Hilliges M, Brodda-Jansen G, Rylander E, Torebjork E. Psychophysical evidence of nociceptor sensitization in vulvar vestibulitis syndrome. Pain. 2001;94:177-183.
FULL TEXT
|
ISI
| PUBMED
25. Bohm-Starke N, Hilliges M, Falconer C, Rylander E. Increased intraepithelial innervation in women with vulvar vestibulitis syndrome. Gynecol Obstet Invest. 1998;46:256-260.
FULL TEXT
|
ISI
| PUBMED
26. Sugiura H, Omoto M, Hirota Y, Danno K, Uehara M. Density and fine structure of peripheral nerves in various skin lesions of atopic dermatitis. Arch Dermatol Res. 1997;289:125-131.
FULL TEXT
|
ISI
| PUBMED
27. Urashima R, Mihara M. Cutaneous nerves in atopic dermatitis: a histological, immunohistochemical and electron microscopic study. Virchows Arch. 1998;432:363-370.
FULL TEXT
|
ISI
| PUBMED
28. Grewe M, Vogelsang K, Ruzicka T, Stege H, Krutmann J. Neurotrophin-4 production by human epidermal keratinocytes: increased expression in atopic dermatitis. J Invest Dermatol. 2000;114:1108-1112.
FULL TEXT
|
ISI
| PUBMED
29. Toyoda M, Nakamura M, Makino T, et al. Nerve growth factor and substance P are useful plasma markers of disease activity in atopic dermatitis. Br J Dermatol. 2002;147:71-79.
FULL TEXT
|
ISI
| PUBMED
30. Romero MI, Rangappa N, Li L, et al. Extensive sprouting of sensory afferents and hyperalgesia induced by conditional expression of nerve growth factor in the adult spinal cord. J Neurosci. 2000;20:4435-4445.
FREE FULL TEXT
31. LaMotte RH, Shain CN, Simone DA, Tsai EFP. Neurogenic hyperalgesia psychophysical studies of underlying mechanisms. J Neurophysiol. 1991;66:190-211.
FREE FULL TEXT
32. Koltzenburg M. Neural mechanisms of cutaneous nociceptive pain. Clin J Pain. 2000;16(3 suppl):S131-S138.
ISI
| PUBMED
33. Bickford RGL. Experiments relating to itch sensation, its peripheral mechanism and central pathways. Clin Sci. 1938;3:377-386.
ISI
34. Simone DA, Alreja M, LaMotte RH. Psychophysical studies of the itch sensation and itchy skin ("alloknesis") produced by intracutaneous injection of histamine. Somatosens Mot Res. 1991;8:271-279.
ISI
| PUBMED
35. Heyer G, Ulmer FJ, Schmitz J, Handwerker HO. Histamine-induced itch and alloknesis (itchy skin) in atopic eczema patients and controls. Acta Derm Venereol (Stockh). 1995;75:348-352.
36. Schmelz M, Hilliges M, Schmidt R, et al. Active "itch fibers" in chronic pruritus. Neurology. 2003;61:567-569.
FREE FULL TEXT
37. Nilsson HJ, Schouenborg J. Differential inhibitory effect on human nociceptive skin senses induced by local stimulation of thin cutaneous fibers. Pain. 1999;80:103-112.
FULL TEXT
|
ISI
| PUBMED
38. Groene D, Martus P, Heyer G. Doxepin affects acetylcholine induced cutaneous reactions in atopic eczema. Exp Dermatol. 2001;10:110-117.
FULL TEXT
|
ISI
| PUBMED
39. Reeh PW, Kress M. Effects of classical algogens. Semin Neurosci. 1995;7:221-226.
FULL TEXT
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